Background: Clostridium difficile infections (CDI) are increasing in incidence and severity, and the Veteran population is at elevated risk of this healthcare-associated infection. Despite prevention initiatives in VA, CDI rates (adjusted for facility complexity and patient mix) have continued to vary widely across VA sites. Antibiotic stewardship (AS) programs have been shown to reduce hospital-onset CDI rates, and so they are a key component of CDI prevention programs. However, it is unknown which AS strategies are most effective in reducing CDI specifically and how to implement these AS strategies effectively. Specific Aims: Our long-term goal is to use implementation science to develop and evaluate interventions to reduce healthcare-associated infections like CDI. We aim to understand the contextual and work system factors that are part of AS interventions and their impact on clinical outcomes. The Agency for Healthcare Research and Quality (AHRQ) has committed funding to our academic affiliate (PI: Safdar) to conduct a randomized controlled trial to 1) measure the impact of a core AS intervention (preprescription authorization, PPA) on reducing CDI rates and 2) use a systems engineering framework to evaluate the contextual, implementation, and work system factors that contribute to clinical outcomes. This Partnered Evaluation Initiative will leverage AHRQ funding to evaluate the clinical and implementation outcomes of a second core AS intervention with the goal of reducing CDI. Here, we will evaluate a prospective audit with feedback (PAF) AS intervention and its implementation in a VA context in order to produce implementation strategies for the specific needs of VA facilities. Our aims for this project are: 1: Evaluate implementation outcomes of a PAF intervention using a blend of the Integrated Promoting Action on Research in Health Services (PARiHS) and Systems Engineering Initiative for Patient Safety (SEIPS) models. 2: Explore the impacts of a core AS intervention (PAF) on clinical outcomes - including CDI rates - in VA settings. 3: Develop and disseminate sustainable recommendations for AS in VA aimed at reduction of CDI. Methods: We will use Mentored Implementation methods to help six VA inpatient units optimize and implement PAF interventions to reduce the use of fluoroquinolones. We will use systems engineering frameworks to evaluate the fidelity, acceptability, and feasibility of the implementations as part of a multiple case study design at each participating unit. We will also conduct an interrupted time series analysis at each site using pre- and post-intervention data to measure the impact of the intervention on clinical outcomes such as CDI rates and antibiotic usage. Impacts: This project will use the iPARiHS and SEIPS frameworks to undertake a complete work systems analysis ? systematically examining implementation barriers and facilitators to AS interventions. By partnering this project with the AHRQ-funded trial, we will develop practical and applicable implementation recommendations for two core AS interventions (PPA and PAF). These implementation recommendations will fill a critical gap in AS program guidelines and will enhance CDI prevention initiatives across VA.